Dendritic spines are highly dynamic and undergo activity-dependent morphological changes which involve the actin cytoskeleton. There is intense interest in the molecular mechanisms that regulate actin cytoskeletal dynamics in spines, because they are believed to be associated with plasticity. Since we have previously shown that the synaptic GDPIGTP exchange factor (GEF) kalirin-7 regulates spine morphogenesis, we hypothesized that mechanisms involved in synaptic development and plasticity also regulate kalirin-7. The short-term goal of the proposed research is to understand the mechanisms that regulate Kalirin-7 in dendritic spines, and thus the mechanisms that regulate spine morphogenesis. The overall goal of the proposed research is to provide a better understanding of how synapses are generated and change, and on the long run, to expand our understanding of the processes of brain development, learning and memory, mental retardation, and aging. We will examine the role of synaptic activity in regulating localization of kalirin-7 to spines and its GEF activity in primary cultures of cortical and hippocampal neurons. Because kalirin-7 may be associated with glutamate receptors, which are involved in synaptic plasticity, we will focus on the role of glutamate receptors in regulating kalirin-7. In addition, we will examine the association of glutamate receptors in complexes with kalirm-7 in neurons and brain. We will also examine the role of phosphorylation in regulation of kalirin-7 GEF activity and localization, with the goal to provide a general outline of the role of phosphorylation in kalirin-7 function. We will delineate the role of tyrosine vs. serine/threonine phosphorylation, and generate initial information about the types of protein kinases involved. Together, these experiments will provide a basis for future studies of regulation of kalirin-7 and spine morphogenesis.